The broad objective of this program is to define the mechanisms that underlie the generation of protective immune responses with the ultimate goal of facilitating the development of more efficacious vaccines. Emphasis is placed on elucidating the mechanisms that can quantitatively or qualitatively enhance immunogenicity and memory in vivo. The individual projects are interactive and complementary and each analyzes a different key component required for generating immunity: (i) antigen presentation (ii) cellular and effector mechanisms and (iii) stability of effector cells and development of long-lived memory. The three projects have the following Aims: Project 1. Mechanisms of Antigen presentation that enhance immunogenicity. The goals of this project are to elucidate the key elements of antigen presentation pathways that influence immunogenicity in vivo and to manipulate these elements to enhance the generation of protective immune responses. The mechanisms involved in generating and presenting peptide- MHC class I and class II complexes in vivo will be elucidated. Methods will be developed for enhancing antigen presentation in animals and the effects on the development of protective immunity will be examined. Project 2. Cellular and effector mechanisms in viral immunization. The objective of this project is to define the mechanisms of protective immunity in an animal model of a viral infection, and the pathophysiologic effects of different effector systems. The role of specific T cell subsets, their differentiation into effector cells and the contribution of specific cytokines will be examined. The potential usefulness of replication defective viruses, in conjunction with engineered antigens (project 1), as approaches for vaccination will be investigated. Project 3. Memory T cell Development. The goals of this project are to examine the stimuli that induce the development of CD4 memory T cells in animals and to elucidate the mechanisms that promote the expansion and maintenance of these populations. The development, survival and stability of effector and memory T cells in vivo will be defined. The roles of antigen, cytokines and costimulators in maintenance and functions of memory T cells will be examined. The impact of the tools nd methodologies developed in projects 1 and 2 on the development of memory will be evaluated.